Project Summary/Abstract Crosslinked Nanosponges for the Topical Treatment of Wound Biofilms The goal of the proposed research is the creation of therapeutics against multidrug-resistant biofilm infections. These infections are very difficult to treat: The refractory nature of biofilm infections make them highly resistant to standard antibiotics, a situation exacerbated by the development of antibiotic-resistant bacteria. In our research we will synergistically integrate the nanomedicine capabilities of Rotello with biofilm expertise of Patel. In preliminary research Rotello has developed crosslinked nanosponges imbibed with essential oil antimicrobials that penetrate and kill biofilm-based bacteria with minimal effect on host cells. Patel has created effective wound biofilm models that allow efficient assessment of therapeutics. In our proposed research we will develop new nanosponge therapeutics and test them against biofilms in vitro, in co-culture with mammalian cells, and finally in vivo. Aim 1: Rotello will fabricate and characterize polymeric nanosponges and optimize their activity against multi-drug resistant biofilms including S. aureus (MRSA) biofilm models. These nanosponges will be tested against mammalian cells in co-culture models, with the goal of maximizing antibacterial efficacy and minimizing mammalian cell toxicity. Aim 2: Rotello will screen therapeutics including antibiotics, quorum sensing inhibitors, and siderophores to create Generation 2 combination antibacterial agents. Aim 3: Patel will perform dosing and pre-clinical mouse studies of the optimized Generation 1 and 2 formulations, determining wound healing activity. Rotello will screen for inflammation.